U.S. patent application number 11/832728 was filed with the patent office on 2008-03-27 for solid forms of (3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone and methods of their use.
Invention is credited to Joseph BARBOSA, Cynthia Anne Fink, Michael Alan Green.
Application Number | 20080076788 11/832728 |
Document ID | / |
Family ID | 38859037 |
Filed Date | 2008-03-27 |
United States Patent
Application |
20080076788 |
Kind Code |
A1 |
BARBOSA; Joseph ; et
al. |
March 27, 2008 |
SOLID FORMS OF
(3'-CHLOROBIPHENYL-4-YL)(1-(PYRIMIDIN-2-YL)PIPERIDIN-4-YL)METHANONE
AND METHODS OF THEIR USE
Abstract
Solid amorphous and crystalline forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
are disclosed, in addition to methods of their use in the treatment
of various diseases and disorders.
Inventors: |
BARBOSA; Joseph;
(Lambertville, NJ) ; Fink; Cynthia Anne; (Lebanon,
NJ) ; Green; Michael Alan; (Easton, PA) |
Correspondence
Address: |
LEXICON PHARMACEUTICALS, INC.
8800 TECHNOLOGY FOREST PLACE
THE WOODLANDS
TX
77381-1160
US
|
Family ID: |
38859037 |
Appl. No.: |
11/832728 |
Filed: |
August 2, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60835677 |
Aug 4, 2006 |
|
|
|
Current U.S.
Class: |
514/275 ;
544/324 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 401/04 20130101; A61P 25/28 20180101 |
Class at
Publication: |
514/275 ;
544/324 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61P 25/00 20060101 A61P025/00; C07D 401/04 20060101
C07D401/04 |
Claims
1. Solid amorphous
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
or a pharmaceutically acceptable salt or solvate thereof.
2-9. (canceled)
10. A crystalline compound, wherein the compound is
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
or a pharmaceutically acceptable salt or solvate thereof.
11. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises a peak at about 4.7 degrees
2.theta..
12. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 9.3 and 18.8
degrees 2.theta..
13. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 19.7 and 22.4
degrees 2.theta..
14. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 23.2 and 27.9
degrees 2.theta..
15. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 29.6 and 32.2
degrees 2.theta..
16. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 32.6 and 37.2
degrees 2.theta..
17. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 41.6 and 42.3
degrees 2.theta..
18. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that comprises peaks at about 9.3, 27.9 and
42.7 degrees 2.theta..
19. The crystalline compound of claim 10, which has an X-ray powder
diffraction pattern that is substantially the same as that shown in
FIG. 1.
20. The crystalline compound of claim 10, which has a Raman
spectrum that is substantially the same as that shown in FIG.
2.
21. The crystalline compound of claim 10, which has a melting point
of about 117.degree. C.
22. Solid
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methan-
one comprising crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl )piperidin-4-yl)methanone
in an amount of at least about 50 weight percent.
23. The solid of claim 22, which comprises crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
in an amount of at least about 75 weight percent.
24. The solid of claim 23, which comprises crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
in an amount of at least about 95 weight percent.
25. A method of preparing crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone,
which comprises: dissolving
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
in ethanol to provide a solution; cooling the solution to a
temperature at which crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
forms; and isolating the crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone.
26. A pharmaceutical dosage form comprising the crystalline
compound of claim 10.
27-29. (canceled)
30. A method of improving the cognitive performance of a patient,
which comprises administering to the patient an effective amount of
the crystalline compound of claim 10.
31. (canceled)
32. The method of claim 30, wherein the cognitive performance is
rapidity of learning, comprehension, reasoning, or memory.
33. A method of treating, managing or preventing a disease or
disorder in a patient, which comprises administering to the patient
an effective amount of the crystalline compound of claim 10.
34. (canceled)
35. The method of claim 33, wherein the disease or disorder is
Alzheimer's disease, autism, a cognitive disorder, dementia, a
learning disorder, or memory loss.
36. The method of claim 35, wherein the learning disorder is
dyslexia, dyscalculia, dysgraphia, dysphasia, or dysnomia.
37. A method of preparing a dosage form, which comprises combining
crystalline
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
with a pharmaceutically acceptable excipient.
38. The method of claim 37, wherein the dosage form is a liquid
dosage form.
Description
[0001] This application claims priority to U.S. provisional patent
application No. 60/835,677, filed Aug. 4, 2006, the entirety of
which is incorporated herein by reference.
1. FIELD OF THE INVENTION
[0002] This invention relates to amorphous and crystalline solid
forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone,
and to methods of their use.
2. BACKGROUND OF THE INVENTION
[0003] Different solid forms of the same compound can have
substantially different properties. For example, the amorphous form
of a drug may exhibit different dissolution characteristics and
different bioavailability patterns than its crystalline form(s),
properties which can affect how the drug must be administered to
achieve optimal effect. Amorphous and crystalline forms of a drug
may also have different handling properties (e.g., flowability,
compressibility), dissolution rates, solubilities and stabilities,
all of which can affect the manufacture of dosage forms.
Consequently, access to multiple forms of a drug is desirable for a
variety of reasons. Moreover, regulatory authorities (e.g., the
U.S. Food and Drug Administration) may require the identification
of all solid (e.g., polymorphic) forms of a new drug substance
before approving products containing it. A. Goho, Science News
166(8):122-123 (2004).
[0004] Compounds may exist in one or more crystalline forms, but
their existence and characteristics cannot be predicted with any
certainty. In addition, no standard procedure exists for the
preparation of all possible polymorphic forms of a compound. And
even after one polymorph has been identified, the existence and
characteristics of other forms can only be determined by additional
experimentation. Id.
3. SUMMARY OF THE INVENTION
[0005] This invention is directed, in part, to amorphous and
crystalline solid forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone,
which is an inhibitor of the Na.sup.+-dependent proline
transporter.
[0006] One embodiment of the invention encompasses pharmaceutical
compositions comprising the solid forms described herein.
[0007] Another embodiment encompasses methods of improving
cognitive performance, and of treating, managing and/or preventing
various diseases and disorders, using solid forms of the
invention.
4. BRIEF DESCRIPTION OF THE FIGURES
[0008] Certain aspects of the invention may be understood with
reference to the attached figures.
[0009] FIG. 1 is a X-ray diffraction pattern of a crystalline solid
form of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone.
The spectrum was obtained using a Shimadzu XRD-6000 diffractometer
configured as follows: X-ray tube[Cu (1.54060 .ANG.), 40.0 kV, 40.0
mA]; scan range [3.00 to 45.0 degrees, 0.0400 degree step size];
count time [1.20 sec].
[0010] FIG. 2 is a FT-Raman spectrum of a crystalline solid form of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone.
The spectrum was obtained using a Bruker RFS100 spectrometer: 1064
nm excitation (100 mW); 64 scans.
5. DETAILED DESCRIPTION OF THE INVENTION
[0011] This invention is directed, in part, to solid amorphous and
crystalline forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone,
which is an inhibitor of the Na.sup.+-dependent proline
transporter. See U.S. patent application Ser. Nos. 11/433,057 and
11/433,626, both filed May 12, 2006. When administered to mice, the
compound has been shown to increase learning and memory.
[0012] This invention is also directed to dosage forms comprising
solid amorphous and crystalline forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone,
and to methods of using solid amorphous and crystalline forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
for the improvement of cognitive performance and for the treatment,
prevention and/or management of diseases and disorders such as
Alzheimer's disease, autism, cognitive disorders, dementia,
learning disorders, and short- and long-term memory loss.
5.1. Definitions
[0013] Unless otherwise indicated, the terms "manage," "managing"
and "management" encompass preventing the recurrence of the
specified disease or disorder, or of one or more of its symptoms,
in a patient who has already suffered from the disease or disorder,
and/or lengthening the time that a patient who has suffered from
the disease or disorder remains in remission. The terms encompass
modulating the threshold, development and/or duration of the
disease or disorder, or changing the way that a patient responds to
the disease or disorder.
[0014] Unless otherwise indicated, the terms "prevent,"
"preventing" and "prevention" contemplate an action that occurs
before a patient begins to suffer from the specified disease or
disorder, which inhibits or reduces the severity of the disease or
disorder, or of one or more of its symptoms. The terms encompass
prophylaxis.
[0015] Unless otherwise indicated, a "prophylactically effective
amount" of a compound is an amount sufficient to prevent a disease
or condition, or one or more symptoms associated with the disease
or condition, or to prevent its recurrence. A prophylactically
effective amount of a compound is an amount of therapeutic agent,
alone or in combination with other agents, which provides a
prophylactic benefit in the prevention of the disease or condition.
The term "prophylactically effective amount" can encompass an
amount that improves overall prophylaxis or enhances the
prophylactic efficacy of another prophylactic agent.
[0016] Unless otherwise indicated, a "therapeutically effective
amount" of a compound is an amount sufficient to provide a
therapeutic benefit in the treatment or management of a disease or
condition, or to delay or minimize one or more symptoms associated
with the disease or condition. A therapeutically effective amount
of a compound is an amount of therapeutic agent, alone or in
combination with other therapies, which provides a therapeutic
benefit in the treatment or management of the disease or condition.
The term "therapeutically effective amount" can encompass an amount
that improves overall therapy, reduces or avoids symptoms or causes
of a disease or condition, or enhances the therapeutic efficacy of
another therapeutic agent.
[0017] Unless otherwise indicated, the terms "treat," "treating"
and "treatment" contemplate an action that occurs while a patient
is suffering from the specified disease or disorder, which reduces
the severity of the disease or disorder, or one or more of its
symptoms, or retards or slows the progression of the disease or
disorder.
[0018] Unless otherwise indicated, the term "include" has the same
meaning as "include, but are not limited to," and the term
"includes" has the same meaning as "includes, but is not limited
to." Similarly, the term "such as" has the same meaning as the term
"such as, but not limited to."
[0019] Unless otherwise indicated, one or more adjectives
immediately preceding a series of nouns is to be construed as
applying to each of the nouns. For example, the phrase "optionally
substituted alky, aryl, or heteroaryl" has the same meaning as
"optionally substituted alky, optionally substituted aryl, or
optionally substituted heteroaryl."
[0020] It should also be noted that any atom shown in a drawing
with unsatisfied valences is assumed to be attached to enough
hydrogen atoms to satisfy the valences. In addition, chemical bonds
depicted with one solid line parallel to one dashed line encompass
both single and double (e.g., aromatic) bonds, if valences permit.
Structures that represent compounds with one or more chiral
centers, but which do not indicate stereochemistry (e.g., with
bolded or dashed lines), encompasses pure stereoisomers and
mixtures (e.g., racemic mixtures) thereof. Similarly, names of
compounds having one or more chiral centers that do not specify the
stereochemistry of those centers encompass pure stereoisomers and
mixtures thereof.
5.2. Forms of
(3'-Chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
[0021] This invention is directed to solid forms of
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone,
the structure of which is depicted below: ##STR1## One embodiment
is directed to a solid amorphous form. Another is directed to a
solid crystalline form.
[0022] A particular crystalline form of the compound has a melting
point of about 117.degree. C. (e.g., .+-.1.5.degree. C.) as
determined by DSC. The form provides a X-ray diffraction pattern
that contains peaks at about 4.7, 9.3, 18.8, 19.7, 22.4, 23.2,
27.9, 29.6, 32.3, 32.6, 37.2, 41.5, 42.3, and/or 42.7 degrees
2.theta.. As those skilled in the art are well aware, the relative
intensities of peaks in a X-ray diffraction pattern of a
crystalline form can vary depending on how the sample is prepared
and how the data is collected. With this in mind, an example of a
X-ray diffraction pattern of this crystalline form is provided in
FIG. 1. An example of an FT-Raman spectrum of this crystalline form
is provided in FIG. 2.
[0023] This particular crystalline form can be prepared by:
dissolving
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
in ethanol (e.g., at a temperature greater than room temperature)
to provide a solution; cooling the solution (or allowing the
solution to cool) to a temperature at which crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
forms; and isolating the crystalline
3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone.
[0024] This invention encompasses solids that are mixtures of both
amorphous and crystalline forms. Certain such solids comprise
crystalline
(3'-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone
in an amount of at least about 50, 75, 80, 85, 90, 95 or 99 weight
percent.
5.3. Methods of Treatment
[0025] One embodiment of this invention encompasses a method of
inhibiting a proline transporter, which comprises contacting a
proline transporter (in vitro or in vivo) with a sufficient amount
of a compound of the invention (i.e. a compound disclosed herein).
Preferred proline transporters are encoded by the human gene
SLC6A7, the murine ortholog thereof, or a nucleic acid molecule
that encodes a proline transporter and that hybridizes under
standard conditions to the full length of either.
[0026] Another embodiment encompasses a method of improving the
cognitive performance of a human patient, which comprises
administering to the patient an effective amount of a compound of
the invention. Examples of improved cognitive performance include
enhanced learning (e.g., learning more quickly), improved
comprehension, improved reasoning, and improved short- and/or
long-term memory.
[0027] Another embodiment encompasses a method of treating,
managing or preventing a cognitive disorder (e.g., difficulty in
thinking, reasoning, or problem solving), memory loss (short- and
long-term), or a learning disorder (e.g., dyslexia, dyscalculia,
dysgraphia, dysphasia, dysnomia), which comprises administering to
the patient an effective amount of a compound of the invention.
[0028] Another embodiment encompasses a method of treating,
managing or preventing a disease or disorder, or a cognitive
impairment associated therewith, in a human patient, which
comprises administering to the patient a therapeutically or
prophylactically effective amount of a compound of the invention.
Examples of diseases and disorders include age-associated memory
impairment, Alzheimer's disease, Attention-Deficit/Hyperactivity
Disorder (ADD/ADHD), autism, Down syndrome, Fragile X syndrome,
Huntington's disease, Parkinson's disease, and schizophrenia.
Additional disorders include adverse sequelae of brain damage
caused by, for example, oxygen starvation, traumatic injury, heart
attack or stroke.
[0029] The invention also encompasses methods of treating,
preventing and managing dementia, including dementia associated
with metabolic-toxic, structural and/or infectious causes.
[0030] Metabolic-toxic causes of dementia include: anoxia; B.sub.12
deficiency; chronic drug, alcohol or nutritional abuse; folic acid
deficiency; hypercalcemia associated with hyperparathyroidism;
hypoglycemia; hypothyroidism; organ system failure (e.g., hepatic,
respiratory, or uremic encephalopathy); and pellagra.
[0031] Structural causes of dementia include: amyotrophic lateral
sclerosis; brain trauma (e.g., chronic subdural hematoma, dementia
pugilistica); brain tumors; cerebellar degeneration; communicating
hydrocephalus; irradiation to frontal lobes; multiple sclerosis;
normal-pressure hydrocephalus; Pick's disease; progressive
multifocal leukoencephalopathy; progressive supranuclear palsy;
surgery; vascular disease (e.g., multi-infarct dementia); and
Wilson's disease.
[0032] Infectious causes of dementia include: bacterial
endocarditis; Creutzfeldt-Jakob disease;
Gerstmann-Straussler-Scheinker disease; HIV-related disorders;
neurosyphilis; tuberculous and fungal meningitis; and viral
encephalitis.
[0033] The amount of solid form administered to a patient will
depend on the route of administration and on the condition being
treated, managed or prevented, and can be readily determined by
physicians. Example dosing regimens include: 150, 600 and 1200
mg/day by oral administration.
5.4. Pharmaceutical Compositions
[0034] This invention encompasses pharmaceutical compositions and
dosage forms comprising solid form of the invention. Pharmaceutical
compositions and dosage forms of this invention may optionally
contain one or more pharmaceutically acceptable carriers or
excipients. Certain pharmaceutical compositions are single unit
dosage forms suitable for oral, topical, mucosal (e.g., nasal,
pulmonary, sublingual, vaginal, buccal, or rectal), parenteral
(e.g., subcutaneous, intravenous, bolus injection, intramuscular,
or intraarterial), or transdermal administration to a patient.
Examples of dosage forms include, but are not limited to: tablets;
caplets; capsules, such as soft elastic gelatin capsules; cachets;
troches; lozenges; dispersions; suppositories; ointments;
cataplasms (poultices); pastes; powders; dressings; creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or
inhalers); gels; liquid dosage forms suitable for oral or mucosal
administration to a patient, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions, oil-in-water emulsions, or a
water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
and sterile solids (e.g., crystalline or amorphous solids) that can
be reconstituted to provide liquid dosage forms suitable for
parenteral administration to a patient.
[0035] The formulation should suit the mode of administration. For
example, oral administration may require enteric coatings to
protect the active ingredient from degradation within the
gastrointestinal tract. In another example, the active ingredient
may be administered in a liposomal formulation to shield it from
degradative enzymes, facilitate transport in circulatory system,
and/or effect delivery across cell membranes to intracellular
sites.
[0036] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the chronic treatment of the
same disease. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease.
These and other ways in which specific dosage forms encompassed by
this invention will vary from one another will be readily apparent
to those skilled in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
6. EXAMPLES
[0037] The compound
(3'-chloro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone
was prepared from an intermediate,
(3'-chloro-biphenyl-4-yl)-piperidine-4-yl-methanone hydrochloride,
as described below.
6.1. Preparation of
(3'-Chloro-biphenyl-4-yl)-piperidine-4-yl-methanone
hydrochloride
[0038] (3'-Chloro-biphenyl-4-yl)-piperidine-4-yl-methanone
hydrochloride was prepared by three different methods, identified
below as A, B and C.
[0039] Method A:
[0040] 3-Chlorophenyl boronic acid (Alfa Aesar, purity 97%)(40.7 g,
261.19 mmol, 1.4 eq) was dissolved in isopropanol (Aldrich, ACS
reagent grade) (800 ml) under nitrogen atmosphere. This was added
to a solution of aqueous potassium carbonate (77 g in 150 ml
water), bis(triphenylphosphine)palladium(II) dichloride
(PdCl.sub.2(PPh.sub.3).sub.2) (0.65 g, 0.93 mmol, 0.5 mol. eq.) and
(4-bromophenyl)(piperidine-4-yl)methanone (50 g, 187 mmol, 1 eq)
were stirred at 80.degree. C. for three hours and deemed complete
by LC/MS. After the reaction mixture cooled down to 50.degree. C.,
it was filtered through celite pad, washed with methanol (1 liter).
The filtrate was diluted with water (200 ml), then the organic
solvent removed under reduced pressure. The resulting crude product
was dissolved in ethyl acetate (800 ml) and washed with 1N sodium
hydroxide (2.times.40 ml) and water (1.times.40 ml).
[0041] The organic layer was stirred with aqueous lactic acid (64 g
of 85% lactic acid in 600 ml of water) at 50.degree. C. for 20
minutes. After the organic layer was separated (solution assay
indicated 8% of product present in the organic layer, which can be
captured by additional lactic acid extraction), the aqueous layer
was washed with ethyl acetate (2.times.100 ml). The aqueous layer
was separated, basified to pH=11 with 25% NaOH (.about.70 ml), and
then extracted with ethyl acetate (2.times.200 ml), dried over
sodium sulfate, filtered and concentrated under reduced pressure to
obtained biaryl product 46.23 g (83%) as a syrup. HPLC indicated
99.4% product and 0.57% of debrominated staring material.
[0042] The above product was dissolved in mixture of ethyl acetate
(900 ml) and ethanol (45 ml) and heated at 50.degree. C. 6M aq. HCl
(40 ml) was added dropwise over a period of ten minutes. After 20
minutes, the reaction mixture was cooled to room temperature, and
stirring was continued for an additional hour. The resulting white
solid was filtered and dried under vacuum at 50.degree. C. for five
hours to afford 49.8 grams of the biaryl HCl salt (80%). HPLC
indicated pure product.
[0043] .sup.1H NMR (DMSO-d.sub.6) .delta.: 1.92(m,4H), 2.52(m,2H),
3.12(m, 2H), 3.82(m,1H), 7.51(m,2H),7.75 (m,1H), 7.82(br s,1H),
7.92(bs d, 2H), 8.12(brd, 2H), 9.0 (br s, 2H). MH.sup.+=300, 302
(about 3:1). Pd: 15 ppm.
[0044] Method B
[0045] A round bottom flask was charged with
(4-bromophenyl)(piperidine-4-yl)methanone (20.0 g, 74.6 mmol),
3-chlorophenyl boronic acid (17.4 g, 111 mmol, 1.5 eq), and
palladium encapsulated catalyst (Aldrich, Pd EnCat-TPP.RTM.,
catalyst species PdCl.sub.2(PPh.sub.3).sub.2) (5.2 g, 0.187 mmol,
0.05 eq). These solids were suspended in isopropanol (570 ml) and
allowed to stir for five minutes. To the mixture was added
potassium carbonate (30.8 g, 224 mmol, 3 eq) dissolved in H.sub.2O
(30 ml). The reaction mixture was heated to 80.degree. C. for 16
hours and deemed complete by LC/MS. The suspension was filtered
through a small bed of Celite.RTM. and the filtrate was
concentrated to dryness. The resulting solids were dissolved in
isopropyl acetate (400 ml) and washed with water (3.times.75 ml).
The organic layer was then cooled to 0.degree. C. (ice/water bath)
and to this stirring solution was added slowly 6 N HCl until solids
crystalized. The solids were filtered and dried in a vacuum oven
for 16 hours at 50.degree. C. to afford 16.9 g of compound (68%
yield) in >98% HPLC purity. MH.sup.-=300, 302 (about 3:1). Pd=3
ppm.
[0046] Method C
[0047] A round bottom flask was charged with
(4-bromophenyl)(piperidine-4-yl)methanone (4.00 g, 14.9 mmol),
3-chlorophenyl boronic acid (3.26 g, 20.9 mmol, 1.4 eq), and
Fibrecat 1029.RTM. (0.70 g, 0.448 mmol, 0.03 eq, Johnson Matthey).
These solids were suspended in isopropanol (68 ml) and allowed to
stir for five minutes. To this stirring solution was added
potassium carbonate (6.18 g, 44.8 mmol, 3 eq.) dissolved in
H.sub.2O (12 ml). The resulting solution was heated to 80.degree.
C. for 16 hours, at which time the reaction was deemed complete by
LC/MS. The reaction mixture was filtered through a small bed of
Celite.RTM. and the filtrate was concentrated to dryness. The
resulting solids were dissolved in isopropyl acetate (100 ml) and
washed with water (3.times.50 ml). The organics were cooled to
0.degree. C., and to this stirring mixture was added slowly 6N HCl
until solids crashed out of solution. The solids were filtered and
dried for 16 hours at 50.degree. C. in a vacuum oven to afford 2.89
g of compound (72%) in >98% HPLC purity. MH.sup.+=300, 302
(about 3:1). Pd: 4 ppm
6.2. Preparation of
(3'-Chloro-biphenyl-4-yl)-(1-pyrimidin-2yl-piperidine-4-yl)-methanone
[0048] A mixture of
(3'-chloro-biphenyl-4-yl)-piperidine-4-yl-methanone hydrochloride
salt (40 g, 119.4 mmol), 2-chloropyrimidine (19 g, 167.16 mmol, 1.4
eq), potassium carbonate (325 mesh, Aldrich) (49.4 g, 358.2 mmol, 3
eq) and acetonitrile (560 ml) were stirred at 60.degree. C. for 14
hours and deemed complete by LC/MS. The reaction mixture was
concentrated, and the residue was dissolved in ethyl acetate (800
ml) and water (200 ml). The aqueous layer was separated and
extracted with ethyl acetate (1.times.200 ml). The organic layers
were combined and washed with brine (1.times.50 ml), dried and
concentrated.
6.3. Crystallization of
(3'-Chloro-biphenyl-4-yl)-(1-pyrimidin-2yl-piperidine-4-yl)-methanone
[0049] The product obtained as described in Example 2 was taken
into ethanol (700 ml) and stirred with a mechanical stirrer at
70.degree. C. After 30 minutes, the solid was completely dissolved.
At that time, the reaction temperature was decreased to 45.degree.
C. and stirred for 4 hours (heterogeneous mixture). The reaction
mixture was then stirred at room temperature for 3 hours. The
resulting white solid was filtered washed with ethanol (50 ml),
dried at 50.degree. C. for 5 hours. This gave the product in 84.4%
yield (33.9 g) as a white solid. 100% pure by HPLC.
[0050] .sup.1H NMR(CDCl.sub.3) .delta.: 1.75(m,2H), 1.92(m,2H),
3.05(m,2H), 3.50(m,1H), 4.75(m,2H), 6.42(t,1H), 7.32(m,2H),
7.4(m,1H), 7.51(s,1H),7.62(d,2H), 7.95(d,2H), 8.22(d,2H).
.sup.13CNMR(CDCl.sub.3): 28.72, 43.79,44.34, 110.2, 125.82, 127.78,
127.81, 128.63, 129.39, 130.62, 135.29, 135.49, 142.03, 144.62,
158.13, 161.93, 202.09. MH.sup.+=378, 380 (about 3:1 ratio). Pd: 2
ppm.
[0051] All patents and patent applications cited above are
incorporated herein by reference in their entireties. The full
scope of the invention is understood with reference to the appended
claims.
* * * * *